The effects of adenosine are mediated through at least four specific cell membrane receptors so far identified and classified as receptors A1, A2A, A2B and A3 belonging to the G protein-coupled receptor family. The A1 and A3 receptors down-regulate cellular cAMP levels through their coupling to G proteins, which inhibit adenylate cyclase. In contrast, A2A and A2B receptors couple to G proteins that activate adenylate cyclase and increase intracellular levels of cAMP. Through these receptors, adenosine regulates a wide range of physiological functions.
Thus, in the cardiovascular system the activation of the A1 receptor protects cardiac tissue from the effects of ischemia and hypoxia (Norton G R et al. Am J Physiol. 1999; 276(2 Pt 2):H341-9; Auchampach J A, Bolli R. Am J Physiol. 1999; 276(3 Pt 2):H1113-6). The potential of A1 antagonists for the treatment of congestive hart failure is well documented in the literature (Jacobson K, Gao Z, Nature Rev. Drug. Disc. 2006; 5, 247-264) and also clinically validated by the positive results of phase II clinical trials with the compounds BG-9719 (Gottlieb S S et al, Circulation, 2002, 105, 1349-1353; Biogen idec, Website), BG-9928 (Greenberg B H et al, Circulation, 2003, 108, Abs 1602) and KW-3902 (Coletta A et al, Eur. J. Heart Failure, 2006, 8, 547-49; Novacardia, Website 2006). In the kidney, adenosine exerts a biphasic action, inducing vasodilatation at high concentrations and vasoconstriction at low concentrations. Thus, adenosine plays a role in the pathogenesis of some forms of acute renal failure that may be ameliorated by A1 receptor antagonists (Costello-Boerrigter L C, et al. Med Clin North Am. 2003 March; 87(2): 475-91; Gottlieb S S., Drugs. 2001; 61(10): 1387-93). Recently the potential of A1 antagonists for the treatment of intradialytic hypotension has been demonstrated in clinical trials (E. Imai; M. Fuji, et al. Kydney International, 2006, 69, 877-883).
Moreover, the novel, potent and selective adenosine A1 receptor antagonist FR194921 exerts both cognitive-enhancing and anxiolytic activity, suggesting the therapeutic potential of such compounds for dementia and anxiety disorders (Maemoto T; Tada M, J. Pharmacol. Sci., 2004, 96, 42-52).
A recent report revealed a strong expression of the adenosine A1 receptor located predominantly to the bronchial epithelium and bronchial smooth muscle. The sensitivity of asthmatics to inhaled adenosine coupled with increased adenosine A1 receptor expression implicates a role for these receptors in the pathophysiology of asthma and other respiratory diseases (Page C, Eur Respir J, 2007, 31(2):311-9).
Some derivatives of the 2-amino 1,3 thiazole are known as adenosine receptor antagonists (Moro S, et al. Med. Res. Rev., 26, 131-159). Some patent applications claimed selective the A2b and A3 (WO9964418, WO0242298, WO05063743) and selective A2a (WO06032273) receptor antagonists based on 2-amino-1,3 thiazole derivatives. One report (Ijzerman P, et al. J. Med. Chem. 2001, 44, 749-762) described selective A1 antagonists based on these structures, but the potency and selectivity published were modest, and the results were obtained using the rat instead the human adenosine receptors.